McKusick type metaphyseal chondrodysplasia, also known as cartilage-hair hypoplasia, is a rare progressive inherited disorder characterized by unusually fine, sparse hair and short stature with abnormally short arms and legs (short-limbed dwarfism). Portions of the long bones of the arms and legs develop abnormally with unusual cartilage formations and subsequent abnormal bone formation at the large (bulbous) end portions (metaphyses) of these long bones (metaphyseal chondrodysplasia). In addition, most individuals with McKusick type metaphyseal chondrodysplasia may exhibit impairment of specialized cells (T-cells) that play an important role in helping the body's immune system to fight infection (cellular immunodeficiency). Affected individuals may also have abnormally low levels of certain white blood cells (neutropenia and lymphopenia); low levels of circulating red blood cells (anemia); and/or increased susceptibility to certain infections, such as chickenpox. In some cases, affected infants may also exhibit improper intestinal absorption of certain necessary nutrients (malabsorption) and/or dental abnormalities such as unusually small teeth (microdontia). Some individuals with the disorder may also have additional physical abnormalities. The range and severity of symptoms vary widely from case to case. McKusick type metaphyseal chondrodysplasia is inherited as an autosomal recessive trait.
McKusick type metaphyseal chondrodysplasia is a rare progressive inherited disorder characterized by unusually fine, sparse hair; short stature with abnormally short arms and legs (short-limbed dwarfism); a variety of additional skeletal malformations; and/or abnormalities of the immune and digestive systems. The range and severity of symptoms associated with the disorder vary widely from case to case.
Many affected infants have abnormally fine, sparse, light-colored hair that, in some cases, may also be brittle. In addition, some affected individuals may have very little scalp hair. The eyebrows, eyelashes, and body hair may also be affected. In rare cases, individuals with the disorder may not exhibit such hair abnormalities.
Individuals with McKusick type metaphyseal chondrodysplasia may exhibit growth deficiency before birth (prenatally). In addition, portions of the long bones of the arms and legs develop abnormally with unusual cartilage formations and subsequent abnormal bone formation at the large (bulbous) end portions (metaphyses) of these long bones (metaphyseal chondrodysplasia). As a result, affected individuals exhibit unusually short arms and legs and short stature (short-limbed dwarfism), findings that typically become apparent during childhood.
Abnormal cartilage and bone formation may also affect other bones of the body, including those of the hands and feet (e.g., metacarpals and metatarsals). As affected individuals age, abnormal cartilage formations in the affected areas may harden into round (bulbous) masses of bone, which may become prominent.
Affected infants may also have small wide hands with abnormally short fingers (brachydactyly), unusually short fingernails and toenails, and/or slightly bowed legs (genu varum). In some cases, the calf bone (fibula) may be disproportionately longer than the shin bone (tibia). In addition, affected children may also exhibit unusually flexible (hyperextensible) joints of the hands, wrists, and/or feet. However, some affected children may be unable to completely extend their elbows.
Additional skeletal abnormalities associated with McKusick type metaphyseal chondrodysplasia may include an abnormal horizontal depression across the lower part of the chest (Harrison’s groove), an unusually prominent breastbone (sternum), flaring of bones of the lower rib cage, and/or abnormal backward (lordosis) and/or side-to-side (scoliosis) curvature of the spine.
In some cases, infants with McKusick type metaphyseal chondrodysplasia may have abnormalities of the head and facial (craniofacial) area. For example, they may have an unusually short, broad head (brachycephaly) and/or dental abnormalities such as unusually small teeth (microdontia).
In many cases, individuals with McKusick type metaphyseal chondrodysplasia may exhibit impairment of certain cells of the immune system (T-cells) that play an important role in helping the body to fight certain infections (cellular immunodeficiency). In addition, individuals with cellular immunodeficiency may have abnormally low levels of certain white blood cells (i.e., neutropenia and lymphopenia). As a result, affected children may have an increased susceptibility to certain infections, particularly chickenpox (varicella). In addition, they may be unable to fight off such infections due to the improper functioning of their immune systems. Affected children may exhibit diminished immune response against foreign substances (diminished hypersensitivity). In addition, in some cases, children with McKusick type metaphyseal chondrodysplasia may also exhibit abnormally low levels of circulating red blood cells (anemia). The degree of anemia may correspond to the severity of immunodeficiency. In individuals with McKusick type metaphyseal chondrodysplasia, the severity of immunodeficiency varies widely from case to case.
Infants with McKusick type metaphyseal chondrodysplasia may also have abnormalities of the digestive system. For example, they may exhibit improper intestinal absorption of certain necessary nutrients (intestinal malabsorption). In addition, in some cases, affected infants may have Hirschsprung’s disease, a disorder in which absence of nerve fibers (ganglia) in the muscle wall of the colon prevents the muscles from efficiently pushing waste materials (feces) through the lower digestive tract. As a result, feces abnormally accumulate within the colon. (For more information on Hirschsprung’s disease, please see the Related Disorders section of this report below.)
In rare cases, some individuals with McKusick type metaphyseal chondrodysplasia appear more prone to developing certain malignancies (e.g., Hodgkin’s disease, lymphoma, or leukemia) than the general population. (For information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
McKusick type metaphyseal chondrodysplasia is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.
Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25%.
Investigators have determined that McKusick type metaphyseal chondrodysplasia may be caused by disruption or changes (mutations) of the mitochondrial RNA-processing endoribonuclease (RMRP) gene located on the short arm (p) of chromosome 9 (9p21-p12). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as “p” and a long arm identified by the letter “q.” Chromosomes are further subdivided into bands that are numbered.
Some cases of McKusick type metaphyseal chondrodysplasia have had parents who were related by blood (consanguineous). All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
The symptoms and findings associated with McKusick type metaphyseal chondrodysplasia (e.g., short stature or the severity of immunodeficiency) may vary greatly from case to case (variable expressivity). In addition, all of the characteristics associated with the disorder may not be manifested in all those who inherit the gene (incomplete penetrance).
According to recent research, T cell deficiency of individuals with McKusick type metaphyseal chondrodysplasia may be due, in part, to increased cell fragmentation and death (apoptosis). More research is needed to determine whether abnormally increased apoptosis is characteristic of a majority of individuals with McKusick type metaphyseal chondrodysplasia.
McKusick type metaphyseal chondrodysplasia is a rare disorder that affects males and females in equal numbers. Approximately 200 cases have been reported in the medical literature. The disorder was first detected in the Old Order Amish population of the United States and Canada. However, it has been seen all over the world, with a higher occurrence in Finnish populations. According to one estimate, the prevalence of McKusick type metaphyseal chondrodysplasia in the Finnish population is 1 in 23,000 births.
In most cases, the diagnosis of McKusick type metaphyseal chondrodysplasia may be made by the second or third year of life. Diagnosis of the disorder may be confirmed by a thorough clinical evaluation, identification of characteristic physical findings, a detailed patient history, and a variety of specialized tests, particularly advanced imaging techniques. These include x-ray studies that may reveal malformation and/or characteristic appearance (e.g., scalloped or cupped) of the end portion of the shafts of the long bones (metaphyses).
Children who are diagnosed with McKusick type metaphyseal chondrodysplasia should receive a complete immunological evaluation to determine whether cellular immunodeficiency, particularly improper T-cell function, may be present. In some cases, blood tests may be conducted to detect low levels of red and/or white blood cells as well as diminished effectiveness of white blood cells. For example, certain white blood cells (lymphocytes) normally respond to phytohemagglutinin (PHA) in laboratory (in vitro) tests. Failed or diminished responsiveness of lymphocytes to PHA may further suggest McKusick type metaphyseal chondrodysplasia Phytohemagglutinin is an antibody formed from a protein substance (lectin) found in certain plants.
The treatment of McKusick type metaphyseal chondrodysplasia is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, physicians who specialize in treating skeletal disorders (orthopedists), physicians who diagnose and treat skin disorders (dermatologists), physicians who specialize in blood disorders (hematologists), dental specialists, speech pathologists, dietitians, physical therapists, and/or other health care professionals may need to systematically and comprehensively plan an affected child's treatment.
Orthopedic techniques, orthopedic surgery, physical therapy, and/or other supportive techniques may help treat certain skeletal abnormalities potentially associated with McKusick type metaphyseal chondrodysplasia, such as limited range of motion of the elbows and legs.
In addition, physicians may regularly monitor affected individuals for hematological abnormalities (i.e., neutropenia, anemia, lymphopenia) potentially associated with McKusick type metaphyseal chondrodysplasia. In some severe cases of neutropenia, anemia, and/or lymphopenia, transfusions of specific blood components (e.g., neutrophils) may be given to help reduce associated symptoms.
Because individuals with McKusick type metaphyseal chondrodysplasia may have an increased susceptibility to certain infections, physicians may closely monitor affected individuals, recommend preventive measures, and immediately institute appropriate treatment should such infections occur. In severe cases of such infections, hospitalization may be required. In addition, physicians may recommend that small pox and live polio vaccinations be avoided.
Some individuals with this disorder may be more prone to developing certain malignancies than the general population. Although this association is uncommon, physicians may closely monitor an affected individual to ensure early detection and appropriate treatment.
Individuals with Hirschsprung's disease may require surgery during early childhood to remove the damaged (i.e., widened [dilated]) portion of the colon and re-connect the undamaged portions of the large intestine (i.e., colon and rectum). In some cases, before this procedure is performed, a temporary opening for the colon may be made in the abdominal wall (colostomy) to allow passage of feces from the body.
Genetic counseling will be of benefit for affected individuals and their families. Other treatment for this disorder is symptomatic and supportive.
In individuals with McKusick type metaphyseal chondrodysplasia who experience severe infection (e.g., a severe case of chickenpox), treatment may include the administration of antiviral agents such as leukocyte interferon or acyclovir.
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FROM THE INTERNET
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:250250; Last Update:9/29/95. Entry Number:156400; Last Edit Date:7/20/95. Entry Number:250400; Last Edit Date 2/19/94.